2-(Omega-substituted alkoxy) benzophenones

ABSTRACT

Novel 2-(omega-substituted alkoxy)benzophenones are described having the formula: WHEREIN R is carbamoyloxy, N-lower-alkylcarbamoyloxy, N,N-diloweralkylcarbamoyloxy, 1,2-dihydroxyethyl, 2-carbamoyloxy-1hydroxyethyl, 2-dioxolanon-4-yl, 2-oxazolidinon-5-yl, 3-methyl-2oxazolidinon-5-yl and 1-hydroxy-2-(o-methoxyphenoxy)ethyl; R1 is halogen, hydrogen, alkoxy, nitro and trifluoromethyl; and n is one and two. The compounds have mild CNS depressant activity as determined in mice and some of the compounds are inhibitors of pepsin proteolysis.

mum States Patent [191 Welstead, Jr.

[ Jan. 28, 1975 Z-(OMEGO-SUBSTITUTED ALKOXY) BENZOPHENONES [75] inventor: William John Welstead, Jr.,

Richmond, Va.

[73] Assignee: A. H. Robins Company,

Incorporated, Richmond, Va.

[22] Filed: June 16, 1972 [2]] Appl. No.: 263,481

[52] US. Cl. 260/482 C, 260/307 C, 260/340.2, 260/591, 424/278, 424/300, 424/331 [51] Int. Cl. C07c 125/06 [58] Field of Search 260/482 C, 591

[56] References Cited OTHER PUBLICATIONS Noller, C. R., Chem. of Organic Cmpds., 2nd Ed., 1960. pp. 161.

Primary ExaminerLorraine A. Weinberger Assistant Examiner-Paul J Killos [57] ABSTRACT Novel 2-(omega-substituted alkoxy)benzophenones are described having the formula:

6 Claims, No Drawings 1 2 Z-(OMEGO-SUBSTITUTED ALKOXY) The method of preparation of one ofthe starting ma- BENZOPHENONES terials, namely, 5-chloro-2-(2-hydroxyethoxy)benzophenone, is a modification of the method described The present invention relates to novel benzophein the literature and the modified procedure is given in nones and is particularly concerned with 2-(omega- 5 Preparation I. substituted)benzophenones, compositions thereof and methods of making and using same. PREPARATION l The invention is especially concerned with novel 5 Ch]0ro 2 (Lhwimwethoxy)benzophenonc Compounds having the formula: A mixture of 60 g. (0.258 mole) of 5-chloro-2 1 l0 hydroxybenzophenone, 48 g. (0.52 mole) of 2- R bromoethanol, 14 g. (0.26 mole) of sodium methoxide and 300 ml. of abs. alcohol was stirred at reflux temper- 2) Formula I ature for 20 hours. Thin layer chromatography indi- 15 cated only about 40 percent product formation. The C( O)CSHS mixture was poured into water, acidified with 3N hydrochloric acid and extracted into benzene. After dryh i R i carbamoyloxy, Nl ing over magnesium sulfate the benzene extracts were alkylcarbamoyloxy N N-dilower.alkylcarbamoyloxy evaporated I0 8.11 Oll Which was taken up into dimethyl- 1 2 dih d h 1 z.carbamoyloxy l hydroxyethy], formamide (200 ml.). To the dimethylformamide soluz di l 4 l Loxazolidinondwl, 3 2 tron was added 75 g. (0.5 mole) of potassium carbonate oxazolidinon-S-yl and l-hydroxy-2-(o-methoxyphenoxand 48 mole) of 2'bromoethanol and the h 1 is halt-wen1 hydrogen, lowelgalkoxy nitro ture was heated at 75C. for six hours. After cooling, and trifluoromethyl; and n is one and two the mixture was filtered and the filtrate was evaporated The novel compounds f the present invention to an oil. Distillation of the oil, l68-l75C./0.2 mm., hibit mild pharmacological CNS depressant activity as gave (78 Percent) of P determined by the neuropharmacological profile in I I I a mice using the method ofS. Irwin (Nodine, H. and Sie- Andlysls' 53m forCmHmClO gler, P. E. (eds.): Animal and Clinical Pharmacologic Techniques in Drug Evaluation, Vol. 1, pp 36-54).

Some of the compounds also inhibit pepsin proteolysis PREPARATION n as determined y the method 3 User, When in the procedure of Preparation 1, 5-chloro-2- B. L., and Summerson, W. H.: Practical Physiological hydroxybenzophenone is replaced by an equal molar Chemistry, McGraw-Hill, New York, 1951, p. 374). amount of:

The term lower-alkyl" in the foregoing Formula I Z-hydroxybenzophenone, and where it appears elsewhere throughout the specifi- 5-methoxy-2-hydroxybenzophenone, cation and claims thereof, includes straight and 5-nitro-2-hydroxybenzophenone, and branched chain radicals of up to eight carbon atoms in- S-trifluoromethyl-Z-hydroxybenzophenone, clusive as exemplified by such groups as methyl, ethyl, there are obtained: propyl, butyl and the like. Lower-alkoxy has the for- 2-(2-hydroxyethoxy)benzophenone, mula O-lower-alkyl. 5-meth oxy-2-(Z-hydroxyethoxy)benzophenone,

5-nitro-2-(2-hydroxyethoxy)benzophenone, and METHOD OF PREPARATION 5-trifluoromethyl-2-(2-hydroxyethoxy)benzophe- The preparation of 2-(w-substituted alkoxy)-5- none. substituted benzophenones (I) may be accomplished The following examples are presented to illustrate by mixing and reacting the appropriately substituted the preparation of compounds of the present invention benzophenone (II) with a reactant B (III) wherein B and they should not be construed as limiting it in spirit can be an isocyanate, a dialkylaminocarbonyl chloride, or in scope. ammonium hydroxide or a reactant having a reactive halide radical. The reaction sequence is illustrated by EXAMPLE 1 the following: 2-(2-Carbamoyloxyethoxy)-5-chlorobenzophenone.

A .H B O--(CH -R 6 5 6H5 II III I wherein R, R and n are as defined herelnabove, A is To a slowly stirred mixture of 10 g. (0.036 mole) of selected from the group consisting of -OCH CH O, 5-chloro-2-(2-hydroxyethoxy)benzophenone and 4.7 O, OCH CHOHCH O- and g. (0.073 mole) of sodium cyanate in 50 ml. of methylene chloride was added, dropwise, 8.8 g. (0.073 mole) OCH CHCH OC(O)O' of trifluoroacetic acid. After stirring for four hours the 2 2 7 mixture was poured into water, the methylene chloride layer was separated, dried over magnesium sulfate and and m is zero or one. evaporated to a solid. Recrystallization from methanol gave 7.3 g. (65 percent) of pure product which melted at 151155C.

Analysis:

Calculated l'or C H ClNO C Found C,

EXAMPLE 2 EXAMPLE 3 5-Chloro-2-l2-(N-methylcarbamoyloxy)ethoxy]benzophenone.

A solution of 12 g. (0.043 mole) of 5-chloro-2-(2- hydroxyethoxy)benzophenone in 50 ml. of benzene containing ml. of pyridine was treated with 10 g. (0.18 mole) of methylisocyanate and stirred overnight. The mixture was washed successively with water, 3N hydrochloric acid and 3N sodium hydroxide. The benzene solution was dried over magnesium sulfate and evaporated to a solid which was recrystallized from isopropyl ether. The yield of product was 11.2 g. (78 percent); melting point 83-90C.

Analysis:

Calculated for C H CINO C,61;17; 11.4.83; N,4.20 Found: C,60.74; H.487; N.4.22

EXAMPLE 4 Analysis:

Calculated for C I-1 0N0 2 C,6 Found: C.6

EXAMPLE 5 5-Chloro-2-[2-(N,N-dimethylcarbamoyloxy)ethoxylbenzophenone.

To a stirred mixture of (0.029 mole) of sodium hydride in 50 ml. of dry benzene was added 8 g. (0.029 mole) of 5-chloro-2-(2-hydroxyethoxy)benzophcnonc. After the evolution of hydrogen had ceased. 3.1 g. (0.029 mole) of dimethylcarbamoyl chloride was added and the mixture was stirred for one hour. The mixture was poured into water and the benzene layer was separated, dried over magnesium sulfate and evaporated to an oil. The oil was crystallized from isopropyl ether, yielding 4.5 g. (45 percent) of product which melted at 6971C.

Analysis:

Calculated for C H CINO; C.62.16;H.5.22;'\1 4.03 Found: C.62.21; H.518; N1 4.08

EXAMPLE 6 When in the procedure of Example 5. 5-chloro-2-(2- hydroxyethoxy)benzophenone is replaced by an equal molar amount of:

5-methoxy-2-(2-hydroxyethoxy)benzophenone. and 2-(2-hydroxyethoxy)benzophenone, there are obtained:

5-methoxy-2-[2-(N,Ndimethylcarbamoyloxy)ethoxy]benzophenone, and

2-[2-(N,N-dimethylcarbamoyloxy)ethoxylbenzophenone.

EXAMPLE 7 5-Chloro-2-(2,3-dihydroxypropoxy)benzophenone.

A stirred mixture of 14.4 g. (0.6 mole) of sodium hydride in 300 ml. of dimethylformamide at 0C.. under a nitrogen atmosphere, was treated dropwise with 1 16 g. (0.5 mole) of 5-chloro-2-hydroxybenzophenone. The mixture was warmed to room temperature until evolution of hydrogen ceased. then 56 g. (0.5 mole) of 3-chloro-l,2-propandio1 in 200 ml. of dimethy1formamide was added. The mixture was heated at 1 10C. for 36 hours, then concentrated. The residual oil was dissolved in benzene and the benzene solution was washed with 50 percent sodium hydroxide followed by washing with water. The benzene solution was dried over magnesium sulfate and evaporated to yield g. of crude product. A 12 g. sample was chromatographed on a column of 300 g. ofmagnesium silicate and eluted with benzeneacetone. The oil from the concentrated eluate weighed 7.5 g. (61 percent). A sample was molecularly distilled for analysis.

Calculated for C H CIO Found Analysis:

EXAMPLE 8 5-methoxy-2-hydroxybenzophenone, and 2-hydroxybenzophenone, there are obtained:

5-meth'oxy-2-(2,3-dihydroxypropoxy)benzophenone, and 5 2-(2,3-dihydroxypropoxy)benzophenone.

EXAMPLE 9 form layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to an oil which solidified on standing. Recrystallization of the crude product from methanol gave 25.5 g. 49 percent) of pure product which melted at l22l24C.

Analysis: Calculated for C,-,H, ,Cl0 C,6l.3 25

6; H.394 Found C .49; H 6

EXAMPLE 10 When in the procedure of Example 9, 5-chloro-2- (2,3-dihydroxypropoxy)benzophenone is replaced by an equal molar amount of:

2-(2,3-dihydroxy'propoxy)benzophenone,

5-methoxy-2-(2,3-dihydroxypropoxy)benzophenone, 5-nitro-2-(2,3-dihydroxypropoxy)benzophenone,

and 5-trifluoromethyl-2-(2,3-dihydroxypropoxy)benzophenone, there are obtained:

2-(2-dioxolanon-4-ylmethoxy)benzophenone, 5-methoxy-2 (2-dioxolanon-4-ylmethoxy)benzophenone, 5-nitro-2-(2 di0xolanon-4-ylmethoxy)benzophenone, and 5-trifluoromethyl-2-(2-dioxolanon-4-ylmethoxy)- benzophenone.

EXAMPLE ll droxide was stirred for 48 hours. The solid product which weighed 7 g. (74 percent) was separated by filtration and after crystallization from benzeneisooctane melted at ll7-119C.

EXAMPLE 12 5-Chloro-2-[2-hydroxy-3-(o-methoxyphenoxy)- propoxy]benzophenone.

A stirred mixture of l 1.6 g. (0.05 mole) of 5-chloro- 2-hydroxybenzophenone, 11 g. (0.05 mole) of lchloro-3-(o-methoxyphenoxy)-2-propanol and 13 g. of potassium hydroxide in 50 ml. of dimethylformamide was heated at C. for 24 hours and then poured into water. The product was extracted into benzene which was dried over magnesium sulfate and evaporated to an oil. The oil was chromatographed on 350 g. of magnesium silicate, eluting with a benzene-acetone mixture. The pure product solidified when the eluate was treated with isooctane. The yield was 8 g. (40 percent). After recrystallization from isooctane the product melted at 8688C.

EXAMPLE l3 5-Chloro-2-(2-oxazolidinon-5-ylmethoxy)benzophenone.

A stirred'mixture of 10 g. (0.043 mole) of 5-chloro- Z-hydroxybenzophenone, 7.7 g. (0.043 mole) of 5- bromomethyl-2-oxazolidinone, 6 g. of potassium carbonate and 60 ml. ofdimethylformamide was heated at C. for 36 hours and then poured into water. The product was extracted into benzene and the benzene extract was dried over magnesium sulfate and evaporated to an oil. The oil was chromatographed on a column containing 350 g. of magnesium silicate, eluting with benzeneacetone mixture to give 5.5 g. of purified oil which solidified. Crystallization of the solid from benzene-ether gave 3.5 g. (35 percent) of'pure product melting at ll5-1l7C.

Analysis:

Calculated for C H CINO C,6l.54; H,4.25; N,4.22 Found C.6l.40; H.449; N.4.37

EXAMPLE l4 5-Chloro-2-[2-(3-methyl-2-oxazolidinon-5- yl)ethoxy]benzophenone.

A stirred mixture of 8.6 g. (0.037 mole) of S-chloro- 2-hydroxybenzophenone, 6g. (0.037 mole) of 3- methyl-5-(2-chloroethyl)-2-oxazolidinone and 5.1 g. (0.037 mole) of potassium carbonate in 30 ml. of dimethylformamide was heated at 85C. for 24 hours. The mixture was poured into water, extracted with benzene and the benzene extract dried over magnesium sulfate. Chromatography of the benzene solution of 350 g. of magnesium silicate and eluting with benzeneacetone, gave 11 g. (83 percent) of oily product. A sample was molecularly distilled for analysis. On standing, the oil solidified which after recrystallization from benzene-isooctane melted at 94-96C.

Analysis:

Calculated for C H ClNmz C.58.37; H.461; N.4.0l 65 Found C,58.47; H,4.69; N390 Analysis: I

Calculated for C,,H, ClNO C, Found:

What is claimed is: l; A compound selected from Z-(omega-substituted alkoxy) benzophenones having the formula:

O(CH R C(O)C H wherein;

R is selected from carbamoyloxy, N-loweralkylcarbamoyloxy, N,N-

diloweralkylcarbamoyloxy and 2-carbamoyloxy-lhydroxyethyl,

chlorobenzophenone. 

2. A compound of claim 1 which is 2-(2-carbamoyloxyethoxy-5-chlorobenzophenone.
 3. A compound of claim 1 which is 5-chloro-2-(2-(N-methylcarbamoyloxy)ethoxy)benzophenone.
 4. A compound of claim 1 which is 2-(2-(N-butylcarbamoyloxy)ethoxy)-5-chlorobenzophenone.
 5. A compound of claim 1 which is 5-chloro-2-(2-(N,N-dimethylcarbamoyloxy)-ethoxy)benzophenone.
 6. A compound of claim 1 which is 2-((3-carbamoyloxy-2-hydroxypropoxy)-5-chlorobenzophenone. 